Administration of the long-acting neuromuscular blocker (NMB) d-tubocurarine (curare) (1a) to induce skeletal muscle relaxation during surgery and facilitate tracheal intubation maneuvers transformed the practice of anesthesia. Savarese et al., Pharmacology of Muscle Relaxants and Their Antagonists. In Anesthesia, 4th ed.; Miller, R. D., Ed.; Churchill Livingstone: New York, 1994; pp 417-488. Since that time a variety of semi-synthetic and synthetic neuromuscular blockers with varying durations of NMB (curare-like) activity became available in the clinic. Id.; Lee, Br. J. Anaesth. 2001, 87, 755-769; Rees et al., Annu. Rep. Med. Chem. 1996, 31, 41-50; Bevan, Pharmacol. Toxicol. 1994, 74, 3-9.
Neuromuscular blockers are categorized both by their mechanism of action (nondepolarizing or depolarizing) and by their duration of action (ultra-short, short-, intermediate-, and long-acting). The maximum clinical duration of such neuromuscular blocker as defined by the FDA is the time for return to 25% of control in a twitch response test after a dose of twice the 95% effective dose (ED95). This maximum duration time for an ultra-short neuromuscular blocker is 8 minutes, for a short neuromuscular blocker the duration is 20 minutes, for an intermediate neuromuscular blocker the duration time is 50 minutes and the duration time for a long acting neuromuscular blocker is greater than 50 minutes. See Bedford, Anesthesiology 1995, 82, 33A.
Examples of these neuromuscular blocking adjuncts to anesthesia include the long-acting agent metocurine (1b), the ultra-short-acting succinylcholine (2), the short-acting relaxant mivacurium (3), and the long-acting agent doxacurium (4).

The benzyltetrahydroisoquinoline-based, therefore relaxants are nondepolarizing neuromuscular blockers.
Succinylcholine (2) is a depolarizing agent. Depolarizing neuromuscular blockers are nicotinic acetylcholine receptor agonists and produce a number of unwanted side-effects associated with their mechanism of action. Naguib et al., Anesthesiology 2002, 96, 202-231; Mahajan, Curr. Anaesth. Crit. Care 1996, 7, 289-294; Belmont, Curr. Opin. Anesthesiol. 1995, 8, 362-366; Durant et al., Br. J. Anaesth. 1982, 54, 195-208. These untoward effects can, in rare instances, include anaphylaxis, hyperkalemia, malignant hyperthermia, and cardiac arrhythmias. More common side-effects of depolarizing neuromuscular blockers include fasciculations, severe muscle pain, increased intraocular pressure, and increased intragastric tension.
Although a variety of long-, intermediate-, and short-acting neuromuscular blockers exist in the clinic, methods for reversing the effects of these neuromuscular blocking agents are slow and give rise to undesirable side effects, some of which can be life-threatening. Hence, new intermediate neuromuscular blockers and new methods for controlling the duration of intermediate neuromuscular blockade are needed.